Targeting Activated Platelets: A Unique and Potentially Universal Approach for Cancer Imaging

Ml, Yap; Jd, McFadyen; Wang, Xiaowei; Na, Zia; Jd, Hohmann; Ziegler, Melanie; Yao, Yihong; Pham, Amy Trinh; Harris, Michele R.; Ps, Donnelly; Hogarth, P. Mark; Ga, Pietersz; Lim, Bora; Peter, Karlheinz

doi:10.7150/thno.19900

Cited by 49 publications

(47 citation statements)

References 28 publications

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“…Our in vitro and in vivo data show that netrin-1, although described as a secreted and diffusible protein, bound to the cell surface and/or extracellular matrix. This observation is in line with previous reports about USMI of secreted frizzled related protein 2, interleukin 16, and GPIIb/IIIa in tumors, and confirms the feasibility of USMI in settings where free-circulating proteins can potentially saturate MBs and prevent immobilization 22 , 48 , 49 . Inter- and intra-tumoral heterogeneity with regard to vascular perfusion rates and functionality of the vascular network are crucial factors for USMI with micrometer-sized contrast agents that are injected and limited to the blood vessels 50 , 51 .…”

Section: Discussionsupporting

confidence: 92%

Ultrasound molecular imaging as a non-invasive companion diagnostic for netrin-1 interference therapy in breast cancer

Wischhusen¹,

Wilson²,

Delcros³

et al. 2018

Theranostics

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In ultrasound molecular imaging (USMI), ligand-functionalized microbubbles (MBs) are used to visualize vascular endothelial targets. Netrin-1 is upregulated in 60% of metastatic breast cancers and promotes tumor progression. A novel netrin-1 interference therapy requires the assessment of netrin-1 expression prior to treatment. In this study, we studied netrin-1 as a target for USMI and its potential as a companion diagnostic in breast cancer models.Methods: To verify netrin-1 expression and localization, an in vivo immuno-localization approach was applied, in which anti-netrin-1 antibody was injected into living mice 24 h before tumor collection, and revealed with secondary fluorescent antibody for immunofluorescence analysis. Netrin-1 interactions with the cell surface were studied by flow cytometry. Netrin-1-targeted MBs were prepared using MicroMarker Target-Ready (VisualSonics), and validated in in vitro binding assays in static conditions or in a flow chamber using purified netrin-1 protein or netrin-1-expressing cancer cells. In vivo USMI of netrin-1 was validated in nude mice bearing human netrin-1-positive SKBR7 tumors or weakly netrin-1-expressing MDA-MB-231 tumors using the Vevo 2100 small animal imaging device (VisualSonics). USMI feasibility was further tested in transgenic murine FVB/N Tg(MMTV/PyMT634Mul) (MMTV-PyMT) mammary tumors.Results: Netrin-1 co-localized with endothelial CD31 in netrin-1-positive breast tumors. Netrin-1 binding to the surface of endothelial HUVEC and cancer cells was partially mediated by heparan sulfate proteoglycans. MBs targeted with humanized monoclonal anti-netrin-1 antibody bound to netrin-1-expressing cancer cells in static and dynamic conditions. USMI signal was significantly increased with anti-netrin-1 MBs in human SKBR7 breast tumors and transgenic murine MMTV-PyMT mammary tumors compared to signals recorded with either isotype control MBs or after blocking of netrin-1 with humanized monoclonal anti-netrin-1 antibody. In weakly netrin-1-expressing human tumors and normal mammary glands, no difference in imaging signal was observed with anti-netrin-1- and isotype control MBs. Ex vivo analysis confirmed netrin-1 expression in MMTV-PyMT tumors.Conclusions: These results show that USMI allowed reliable detection of netrin-1 on the endothelium of netrin-1-positive human and murine tumors. Significant differences in USMI signal for netrin-1 reflected the significant differences in netrin-1 mRNA & protein expression observed between different breast tumor models. The imaging approach was non-invasive and safe, and provided the netrin-1 expression status in near real-time. Thus, USMI of netrin-1 has the potential to become a companion diagnostic for the stratification of patients for netrin-1 interference therapy in future clinical trials.

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Section: Discussionsupporting

confidence: 92%

Ultrasound molecular imaging as a non-invasive companion diagnostic for netrin-1 interference therapy in breast cancer

Wischhusen¹,

Wilson²,

Delcros³

et al. 2018

Theranostics

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“…Irrespective of the coupling tracer, this innovative approach allowed us to individuate activated platelets within the tumor microenvironment with high specificity, and sensitivity and give an accurate anatomical view of the tumor itself. The study was carried out in four different human tumor xenograft mouse models, including SKBr3 and MDA-MB-231 breast cancer, HT-1080 fibrosarcoma, and Ramos Burkitt’s lymphoma [ 130 ]. Further studies are needed using these GPIIb/IIIa-based contrast agents to confirm their possible use as an auxiliary non-invasive method for the detection and imaging of cancer and metastatic lesions.…”

Section: Effects Of Antiplatelet Agents In Cancermentioning

confidence: 99%

Antithrombotic Agents and Cancer

Bruno,

Dovizio,

Tacconelli

et al. 2018

Cancers

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Platelet activation is the first response to tissue damage and, if unrestrained, may promote chronic inflammation-related cancer, mainly through the release of soluble factors and vesicles that are rich in genetic materials and proteins. Platelets also sustain cancer cell invasion and metastasis formation by fostering the development of the epithelial-mesenchymal transition phenotype, cancer cell survival in the bloodstream and arrest/extravasation at the endothelium. Furthermore, platelets contribute to tumor escape from immune elimination. These findings provide the rationale for the use of antithrombotic agents in the prevention of cancer development and the reduction of metastatic spread and mortality. Among them, low-dose aspirin has been extensively evaluated in both preclinical and clinical studies. The lines of evidence have been considered appropriate to recommend the use of low-dose aspirin for primary prevention of cardiovascular disease and colorectal cancer by the USA. Preventive Services Task Force. However, two questions are still open: (i) the efficacy of aspirin as an anticancer agent shared by other antiplatelet agents, such as clopidogrel; (ii) the beneficial effect of aspirin improved at higher doses or by the co-administration of clopidogrel. This review discusses the latest updates regarding the mechanisms by which platelets promote cancer and the efficacy of antiplatelet agents.

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“…Addressing a major clinical need, we provide proof of concept of the therapeutic efficacy of our novel ADC in treating both primary tumor and preventing metastasis using a murine model of the difficult to treat triple negative breast cancer. Moreover, we have previously established the ability of the activated platelet-specific scFv for imaging a broad range of tumors 15 which raises the prospect of an integrated approach for cancer diagnosis and therapy, by utilizing molecular imaging as a means to detect tumor-associated platelets, and therefore predict those likely to respond to platelet-targeted therapy. Together, these findings demonstrate the broad potential of our unique activated platelet-targeting approach as a novel theranostic anti-cancer strategy, especially for cancers that do not express specific molecular epitopes suitable for therapeutic targeting.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, upon platelet activation, GPIIb/IIIa undergoes a confirmation change such that it adopts a high affinity conformation for ligand binding 14. Indeed, we recently provided proof of concept that the high affinity conformation of GPIIb/IIIa on activated platelets can serve as a molecular targeting epitope for the tumor microenvironment in several types of cancers in mice and humans 15. Therefore, targeting activated platelets in the tumor microenvironment, using a highly abundant and specific epitope, represents a novel approach for the targeted delivery of tumor directed chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Activated platelets in the tumor microenvironment for targeting of antibody-drug conjugates to tumors and metastases

Yap¹,

McFadyen²,

Wang³

et al. 2019

Theranostics

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Rationale : Platelets are increasingly recognized as mediators of tumor growth and metastasis. Hypothesizing that activated platelets in the tumor microenvironment provide a targeting epitope for tumor-directed chemotherapy, we developed an antibody-drug conjugate (ADC), comprised of a single-chain antibody (scFv) against the platelet integrin GPIIb/IIIa (scFv GPIIb/IIIa ) linked to the potent chemotherapeutic microtubule inhibitor, monomethyl auristatin E (MMAE). Methods : We developed an ADC comprised of three components: 1) A scFv which specifically binds to the high affinity, activated integrin GPIIb/IIIa on activated platelets. 2) A highly potent microtubule inhibitor, monomethyl auristatin E. 3) A drug activation/release mechanism using a linker cleavable by cathepsin B, which we demonstrate to be abundant in the tumor microenvironment. The scFv GPIIb/IIIa -MMAE was first conjugated with Cyanine7 for in vivo imaging. The therapeutic efficacy of the scFv GPIIb/IIIa -MMAE was then tested in a mouse metastasis model of triple negative breast cancer. Results : In vitro studies confirmed that this ADC specifically binds to activated GPIIb/IIIa, and cathepsin B-mediated drug release/activation resulted in tumor cytotoxicity. In vivo fluorescence imaging demonstrated that the newly generated ADC localized to primary tumors and metastases in a mouse xenograft model of triple negative breast cancer, a difficult to treat tumor for which a selective tumor-targeting therapy remains to be clinically established. Importantly, we demonstrated that the scFv GPIIb/IIIa -MMAE displays marked efficacy as an anti-cancer agent, reducing tumor growth and preventing metastatic disease, without any discernible toxic effects. Conclusion : Here, we demonstrate the utility of a novel ADC that targets a potent cytotoxic drug to activated platelets and specifically releases the cytotoxic agent within the confines of the tumor. This unique targeting mechanism, specific to the tumor microenvironment, holds promise as a novel therapeutic approach for the treatment of a broad range of primary tumors and metastatic disease, particularly for tumors that lack specific molecular epitopes for drug targeting.

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Targeting Activated Platelets: A Unique and Potentially Universal Approach for Cancer Imaging

Cited by 49 publications

References 28 publications

Ultrasound molecular imaging as a non-invasive companion diagnostic for netrin-1 interference therapy in breast cancer

Ultrasound molecular imaging as a non-invasive companion diagnostic for netrin-1 interference therapy in breast cancer

Antithrombotic Agents and Cancer

Activated platelets in the tumor microenvironment for targeting of antibody-drug conjugates to tumors and metastases

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